EFFECT OF MULTIPLE DOSES OF KETOCONAZOLE ON CYTOCHROME P450 3A ACTIVITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cytochrome P450 (CYP) 3A enzymes are the most abundant CYP enzymes in adult human liver and small intestine. The CYP3A enzymes are involved in the biotransformation of more than 50% of all metabolized drugs. Many drug-drug interactions (DDI) observed clinically result from altering the activities of these enzymes. Ketoconazole is a strong inhibitor of CYP3A activity in vivo and results in many DDIs but it is unclear whether this effect is dose dependent within the range of doses commonly employed therapeutically. Simulations of clinical trials have suggested that patients may receive the same therapeutic benefit from ketoconazole and less drug interactions at 200 mg twice a day compared to 400 mg once a day for one week. However, the DDI potential of these dosing strategies for ketoconazole have not been directly compared in humans. We plan to determine the effect of ketoconazole 400 mg QD and 200 mg BID on hepatic and intestinal CYP3A activity using midazolam as a prototypical CYP3A substrate. Ketoconazole is a more potent inhibitor of CYP3A4 than CYP3A5 and the latter enzyme is polymorphically expressed (33% of Caucasians and 70% of African Americans). We therefore plan to examine whether the inhibitory potency of ketozonazole is dependent on the presence of genotypes that allow CYP3A5 expression. This will be a cross-over study in 24 healthy volunteers.